3 Search Results

Abstract Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA _A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr.more » Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 ^−/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.« less

Introduction When treatment of status epilepticus (SE) is delayed, seizures become self‐sustaining and refractory to benzodiazepine therapy. Chemical warfare nerve agents (CWNAs), such as soman(GD), increase acetylcholine through inhibition of acetylcholine sterase and can lead to SE if seizures are not treated quickly and controlled. Prolonged seizures may lead to extensive neuropathology, spontaneous recurrent seizures and long‐term performance deficits. To identify a better treatment against pharmacoresistant seizures caused by GD exposure, we are using combinations of drugs aimed at reversing the effects of maladaptive receptor trafficking that follows CWNA exposure. Methods Rats were implanted with telemetry transmitters for continuous monitoringmore » of EEG, body temperature and activity. After surgical recovery, rats were exposed to 1.2 LD ₅₀ GD and treated 1 min later with atropine sulfate and the oxime HI‐6 and then 40 min after seizure onset with the anticonvulsant phenobarbital with or without the NMDA antagonist ketamine (PHE/KET), the benzodiazepine midazolam (PHE/MDZ) or a combination of all three drugs (PHE/KET/MDZ).Two weeks after exposure, rat brains were sectioned and stained for neuropathology assessments. Results Triple therapy with PHE/KET/MDZ reduced total time spent in seizures (SE +early recurrent seizures) in the first 72 h and reduced the number of spontaneous recurrent seizures compared to midazolam monotherapy. Tripletherapy also reduced the duration of toxic signs in the hours following GD‐exposure and prevented the development of hyperactivity that occurs in the weeks following exposure compared to GD/MDZ monotherapy. In addition, tripletherapy reduced loss of neurons in the piriform cortex and thalamus compared to GD/MDZ monotherapy. Conclusion Triple therapy with PHE/KET/MDZ hadanticonvulsant, antiepileptic, and neuroprotective effects compared with midazolammonotherapy in GD‐exposed rats. Triple therapy may be a highly effective approach against pharmacoresistant seizures, such as those caused by GD exposure, and may allow for administration of lower doses, resulting in fewer side effects than are often seen with large doses of individual drug therapies. Disclaimer: The views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act of 1966 (P.L. 89‐544), as amended. Support or Funding Information KatieWalker, Erica Kundrick and Sean O'Brien were supported in part by an appointment to the Research Participation Program for the U.S. Army Medical Research and Materiel Command administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command. This research was supported by the NIH U01 to Dr. Claude Wasterlain.« less